[Research of image spectrometer using linear variable interference filter].
In the present work we have designed a small-size portable imaging spectrometer using linear variable interference filter, with CCD camera as picture sensor, and micromotion stage to bring along interference filter which scan across every pixel of CCD array. The difference column pixel in the picture which we get at every step is monocolour partial image under different wavelength, with the step by step, these column monocolour pixels change the wavelength. And finally we reassembled these images and get the whole monocolour image with different wavelength. The interval of sweep step length decided by the required spectrum resolution and the required wavelength interval of different pictures. The experiment demonstrated the resolution of this spectrometer is about 16 nm, but that major reason of the limiting resolution is the band width of the linear variable interference filter. The spatial resolution of the instrument ultimately decided by CCD, filter and imaging lens. This spectrometer has some characters such as compact structure, higher spatial resolution, higher spectrum resolution, higher scan rate and so on. Furthermore, an application of this instrument in distinguishing from camouflage have been showed.


Biosynthesis of 2-Phenylethanol in Rose Petals Is Linked to the Expression of One Allele of RhPAAS.
Floral scent is one of the most important characters in horticultural plants. Roses (Rosa spp.) have been cultivated for their scent since antiquity. However, probably by selecting for cultivars with long vase life, breeders have lost the fragrant character in many modern roses, especially the ones bred for the cut flower market. The genetic inheritance of scent characters has remained elusive so far. In-depth knowledge of this quantitative trait is thus very much needed to breed more fragrant commercial cultivars. Furthermore, rose hybrids harbor a composite genomic structure, which complexifies quantitative trait studies. To understand rose scent inheritance, we characterized a segregating population from two diploid cultivars, Rosa × hybrida cv H190 and Rosa wichurana, which have contrasting scent profiles. Several quantitative trait loci for the major volatile compounds in this progeny were identified. One among these loci contributing to the production of 2-phenylethanol, responsible for the characteristic odor of rose, was found to be colocalized with a candidate gene belonging to the 2-phenylethanol biosynthesis pathway: the PHENYLACETALDEHYDE SYNTHASE gene RhPAAS An in-depth allele-specific expression analysis in the progeny demonstrated that only one allele was highly expressed and was responsible for the production of 2-phenylethanol. Unexpectedly, its expression was found to start early during flower development, before the production of the volatile 2-phenylethanol, leading to the accumulation of glycosylated compounds in petals.


DLA class II alleles are associated with risk for canine symmetrical lupoid onychodystrophy [corrected](SLO).
Symmetrical lupoid onychodystrophy (SLO) is an immune-mediated disease in dogs affecting the claws with a suggested autoimmune aethiology. Sequence-based genotyping of the polymorphic exon 2 from DLA-DRB1, -DQA1, and -DQB1 class II loci were performed in a total of 98 SLO Gordon setter cases and 98 healthy controls. A risk haplotype (DRB1*01801/DQA1*00101/DQB1*00802) was present in 53% of cases and 34% of controls and conferred an elevated risk of developing SLO with an odds ratio (OR) of 2.1. When dogs homozygous for the risk haplotype were compared to all dogs not carrying the haplotype the OR was 5.4. However, a stronger protective haplotype (DRB1*02001/DQA1*00401/DQB1*01303, OR = 0.03, 1/OR = 33) was present in 16.8% of controls, but only in a single case (0.5%). The effect of the protective haplotype was clearly stronger than the risk haplotype, since 11.2% of the controls were heterozygous for the risk and protective haplotypes, whereas this combination was absent from cases. When the dogs with the protective haplotype were excluded, an OR of 2.5 was obtained when dogs homozygous for the risk haplotype were compared to those heterozygous for the risk haplotype, suggesting a co-dominant effect of the risk haplotype. In smaller sample sizes of the bearded collie and giant schnauzer breeds we found the same or similar haplotypes, sharing the same DQA1 allele, over-represented among the cases suggesting that the risk is associated primarily with DLA-DQ. We obtained conclusive results that DLA class II is significantly associated with risk of developing SLO in Gordon setters, thus supporting that SLO is an immune-mediated disease. Further studies of SLO in dogs may provide important insight into immune privilege of the nail apparatus and also knowledge about a number of inflammatory disorders of the nail apparatus like lichen planus, psoriasis, alopecia areata and onycholysis.


The Challenge of Developing Autophagy Inhibition as a Therapeutic Strategy.
The finding that cancer chemotherapeutic drugs and ionizing radiation often promote autophagy has provided the foundation for clinical trials combining autophagy-blocking agents with antitumor drugs and radiation. The premise driving these trials is that therapy-induced autophagy is cytoprotective; consequently, inhibition of autophagy is anticipated to sensitize malignancies to therapy. However, it is well-established that autophagy may also mediate the toxicity of antitumor drugs while evidence also exists for a nonprotective function of autophagy. Consequently, given that it cannot be predicted what form autophagy will take upon treatment with chemotherapy or radiation, the current ongoing clinical trials are likely to generate contradictory or inconsistent results, with the potential consequence that autophagy inhibition could be dismissed as therapeutic strategy based on what are essentially false-negative outcomes. Appropriate interpretation of the outcomes of these trials would require knowledge as to whether the drugs or radiation used promote the cytoprotective form of autophagy in the tumor cells as well as whether the chloroquine or hydroxychloroquine actually inhibit the autophagy. Ultimately, it will be necessary to identify those patients for whom the strategy of autophagy inhibition would be anticipated to improve the response to therapy. However, this is currently not feasible in the absence of appropriate bioassays or predictive markers for characterization of the autophagy or the effectiveness of pharmacologic approaches for autophagy inhibition in the clinic. Cancer Res; 76(19); 5610-4. ©2016 AACR.


Neurokinin A and B: potent vasodilators in the canine forelimb.
Neurokinin A and neurokinin B may play a role in control of the peripheral circulation in either physiological or pathophysiological conditions. We have infused these peptides intra-arterially at three infusion rates each to assess their actions on vascular pressures, blood flows and total and segmental resistances in skin and skeletal muscle in the canine forelimb. Neurokinin A infusions (.01, .1, and 1 micrograms/min) decreased total forelimb resistance; transiently, 26% and 57%, respectively. The decrease in resistance was equally distributed between the skin and skeletal muscle circulations and was manifest in both large artery and small vessel resistances. Systemic and forelimb arterial pressures were decreased in a dose-dependent manner. Neurokinin B infusions (.5, 1 and 5 micrograms/min) decreased total forelimb resistance 29%, 31%, and 52%, respectively. The decrease in resistance was equally distributed between the skin and skeletal muscle circulations and was the result of decreases in both large artery and small vessel resistances. Systemic and forelimb arterial pressures were decreased in a dose-dependent manner. The potent effect of neurokinins on vascular resistance and their concentration in perivascular nerves innervating the resistance vessels of the circulation suggests a potential role for these neuropeptides in circulatory control.


Percutaneous fluoroscopically-guided transcervical retrograde access facilitates successful thoracic duct embolization after failed antegrade transabdominal access.
The purpose of this study was to demonstrate the feasibility of percutaneous fluoroscopically-guided transcervical retrograde access into the thoracic duct following unsuccessful transabdominal cisterna chyli cannulation to perform thoracic duct embolization for the treatment of chylothorax. Five patients, including three (60%) women and two (40%) men, with median age of 62 years, underwent percutaneous transcervical thoracic duct access and embolization after failed transabdominal cisterna chyli cannulation for the treatment of chylothorax. In all patients, fluoroscopically-guided percutaneous transcervical retrograde access into the distal thoracic duct was achieved using a 21-gauge needle and an 0.018-inch wire. Following advancement of a microcatheter, retrograde lymphangiography was performed to identify the location of thoracic duct injury. A combination of 2:1 ethiodized oil to cyanoacrylate mixtures, platinum microcoils, or stent-grafts were used to treat the chylous leaks. Technical successes, procedure durations, fluoroscopy times, blood losses, immediate adverse events, clinical successes, and follow-up durations were recorded. Technical success was defined as cannulation of the distal thoracic duct using a transcervical approach followed by treatment of the thoracic duct injury. Adverse events were classified according to the Society of Interventional Radiology guidelines. Clinical success was defined as resolution of the presenting chylothorax. Percutaneous transcervical retrograde thoracic duct access and treatment was technically successful in all patients (n=5). Median procedure duration was 173 minutes (range: 136-347 minutes) with a median fluoroscopy time of 94.7 minutes (range: 47-125 minutes). Median blood loss was 10 mL (range: 5-20 mL). No minor or major adverse occurred. Clinical success was achieved in all patients (n=5). Median follow-up was 372 days (range: 67-661 days). Percutaneous fluoroscopically- guided transcervical retrograde thoracic duct access is an effective and safe method to perform thoracic duct embolization following unsuccessful transabdominal cisterna chyli cannulation for the treatment of chylothorax.


Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes.
Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potential fatal emergency. A synchronous bilateral adrenalectomy (SBA) is effective in recovering hypercortisolism. However, specific indications for an SBA are not available. We aimed to evaluate the outcome of patients who underwent an SBA and to identify biomarkers able to predict the requirements of an SBA. A mono-centric and longitudinal study was conducted on 19 consecutive patients who underwent SBA for ACTH-dependent hypercortisolism between December 2003 and December 2017. This study population was compared to two control groups composed of patients cured after the resection of the ACTH secreting pituitary adenoma (Group A: 44 patients) and of the ACTH-secreting neuroendocrine tumours (Group B: 8 patients). Short- or long-term SBA complications or the recurrence of hypercortisolism did not occur. A single patient experienced Nelson syndrome. Clinical features after SBA showed improvement in the glico-metabolic assessment, hypertension, bone metabolism and the occurrence of hypokalaemia and infections. The younger the age at the time of Cushing's disease diagnosis, the longer the duration of active hypercortisolism, higher values of plasmatic ACTH and Cortisol (1 month after pituitary neurosurgery) and higher values of Ki67 in pituitary adenomas were detected in this study population as compared to Group A. SBA is an effective and safe treatment for patients with unmanageable ACTH-dependent hypercortisolism. A multidisciplinary team in a referral centre with a high volume of patients is strongly recommended for the management of these patients and the identification of patients, for better surgical timing.


Breast cancer and sentinel lymph node micrometastases: indications for lymphadenectomy and literature review.
An increasingly early diagnosis for discovering breast cancer, an improvement of surgical procedures with refining techniques for research and study of sentinel node, currently allow a more conservative surgical approach. Association with suitable chemo-radiotherapy allows a good control of breast disease. Our study, although modest, was carried out on 63 patients suffering from breast cancer, who underwent surgical treatment with assessment of sentinel lymph node. Aim of study was to establish the most correct strategy in the presence of isolated tumor cells (ITC) and/or micro-metastases of sentinel lymph node. Many studies have been carried out to find which was the most appropriate treatment, nevertheless, in the absence of univocal guidelines, we prefer to proceed to axillary dissection, though the topic is very debated and controversial. Following this strategy we obtained quite satisfactory results.


Histidine-rich stabilized polyplexes for cMet-directed tumor-targeted gene transfer.
Overexpression of the hepatocyte growth factor receptor/c-Met proto oncogene on the surface of a variety of tumor cells gives an opportunity to specifically target cancerous tissues. Herein, we report the first use of c-Met as receptor for non-viral tumor-targeted gene delivery. Sequence-defined oligomers comprising the c-Met binding peptide ligand cMBP2 for targeting, a monodisperse polyethylene glycol (PEG) for polyplex surface shielding, and various cationic (oligoethanamino) amide cores containing terminal cysteines for redox-sensitive polyplex stabilization, were assembled by solid-phase supported syntheses. The resulting oligomers exhibited a greatly enhanced cellular uptake and gene transfer over non-targeted control sequences, confirming the efficacy and target-specificity of the formed polyplexes. Implementation of endosomal escape-promoting histidines in the cationic core was required for gene expression without additional endosomolytic agent. The histidine-enriched polyplexes demonstrated stability in serum as well as receptor-specific gene transfer in vivo upon intratumoral injection. The co-formulation with an analogous PEG-free cationic oligomer led to a further compaction of pDNA polyplexes with an obvious change of shape as demonstrated by transmission electron microscopy. Such compaction was critically required for efficient intravenous gene delivery which resulted in greatly enhanced, cMBP2 ligand-dependent gene expression in the distant tumor.


Anatomical and functional assemblies of brain BOLD oscillations.
Brain oscillatory activity has long been thought to have spatial properties, the details of which are unresolved. Here we examine spatial organizational rules for the human brain oscillatory activity as measured by blood oxygen level-dependent (BOLD) signal. Resting-state BOLD signal was transformed into frequency space (Welch's method) and averaged across subjects, and its spatial distribution was studied as a function of four frequency bands, spanning the full BOLD bandwidth. The brain showed anatomically constrained distribution of power for each frequency band. This result was replicated on a repository dataset of 195 subjects. Next, we examined larger-scale organization by parceling the neocortex into regions approximating Brodmann areas (BAs). This indicated that BAs of simple function/connectivity (unimodal), versus complex properties (transmodal), are dominated by low-frequency BOLD oscillations, and within the visual ventral stream we observe a graded shift of power to higher-frequency bands for BAs further removed from the primary visual cortex (increased complexity), linking BOLD frequency properties to hodology. Additionally, BOLD oscillation properties for the default mode network demonstrated that it is composed of distinct frequency-dependent regions. When the same analysis was performed on a visual-motor task, frequency-dependent global and voxelwise shifts in BOLD oscillations could be detected at brain sites mostly outside those identified with general linear modeling. Thus, analysis of BOLD oscillations in full bandwidth uncovers novel brain organizational rules, linking anatomical structures and functional networks to characteristic BOLD oscillations. The approach also identifies changes in brain intrinsic properties in relation to responses to external inputs.


Use of balloon pull-through technique to assist in CardioSEAL device closure of patent foramen ovale.
CardioSEAL device closure of patent foramen ovale (PFO) has been advocated for the treatment of patients with cryptogenic stroke. Using the standard delivery technique, partial deployment of the CardioSEAL device can occur, especially in patients with a thick septum secundum and/or long PFO tunnel. We hypothesized that using a left atrial-to-right atrial balloon pull-through to make the septum primum incompetent would result in improved final device position regardless of septal thickness or tunnel length. Catheterization reports, cineangiograms, and transesophageal echocardiograms of 51 patients who underwent CardioSEAL device closure of PFO between March 2000 and August 2002 were retrospectively reviewed. Group 1 (n = 21) included patients with CardioSEAL placement using the standard technique and group 2 (n = 30) included patients with CardioSEAL placement using the balloon pull-through technique. There were no differences between the groups in terms of age (43.6 vs. 45.3 years; P = NS), weight (83.3 vs. 89.9 kg; P = NS), septum secundum thickness (6.4 vs. 7.0 mm; P = NS), PFO tunnel length (15.5 vs. 13.1 mm; P = NS), or device size. In group 1, 4/21 (19%) had partial deployment of the CardioSEAL device, while in group 2, no partial CardioSEAL deployment (0/30) was observed. No complications were associated with the balloon pull-through technique. We conclude that the left atrial-to-right atrial balloon pull-through technique is safe and may allow for better final position of the CardioSEAL device during PFO closure.


Influence of substrate interaction and confinement on electric-field-induced transition in symmetric block-copolymer thin films.
In the present work, we study morphologies arising due to competing substrate interaction, electric field, and confinement effects on a symmetric diblock copolymer. We employ a coarse-grained nonlocal Cahn-Hilliard phenomenological model taking into account the appropriate contributions of substrate interaction and electrostatic field. The proposed model couples the Ohta-Kawasaki functional with Maxwell equation of electrostatics, thus alleviating the need for any approximate solution used in previous studies. We calculate the phase diagram in electric-field-substrate strength space for different film thicknesses. In addition to identifying the presence of parallel, perpendicular, and mixed lamellae phases similar to analytical calculations, we also find a region in the phase diagram where hybrid morphologies (combination of two phases) coexist. These hybrid morphologies arise either solely due to substrate affinity and confinement or are induced due to the applied electric field. The dependence of the critical fields for transition between the various phases on substrate strength, film thickness, and dielectric contrast is discussed. Some preliminary 3D results are also presented to corroborate the presence of hybrid morphologies.


Competitive foraging in the social spider Stegodyphus dumicola.
Reproductive skew models have greatly enhanced the study of sociality but are applicable only to societies where the aim of the members of the group is to reproduce. In 'foraging societies', where the aim of the members of the group is to grow, quite different parameters will govern the form that the societies take. We examined factors that influence the structure of foraging groups in the social spider Stegodyphus dumicola (Eresidae). In particular, we examined food distribution and consumption within groups, and how this related to predictions derived from two models. One model indicates that colonies in which individuals compete for resources via interference competition are more likely to survive than those in which individuals divide resources using scramble competition. The second model predicts the proportions of hunters, cheaters and scavengers expected in foraging groups. We found that food was not distributed evenly among group members, and that spiders that fed primarily on the head and thorax of the prey during the middle of a feeding event gained the most body mass. Spiders even lost mass if they fed only in the last hour of a foraging event. Large spiders had a competitive advantage (via interference competition) in obtaining preferred positions, and could ingest food faster than small spiders. Distributing food among colony members in this manner could cause large size differences between colony members, as predicted by the models. The implications of competitive foraging for sociality are discussed. Copyright 1999 The Association for the Study of Animal Behaviour.


Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: response to immunosuppressive therapy.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder for which the gene (AIRE) has recently been identified on chromosome 21q22.3. We present the mutational analyses of a French-Canadian family with APECED, in which there are two affected siblings, as well as the response to cyclosporine A(CyA) therapy in the index patient, the eldest sibling. Haplotype analysis suggested compound heterozygozity at the AIRE locus. Direct sequencing of exon 8 revealed a previously described mutation, a 13-bp deletion (1085-1097) of maternal origin, found in the index patient, her affected sister, and her unaffected sister. A novel missense mutation characterized by a T-->G transversion at nucleotide position 398, resulting in a leu-->arg amino acid substitution (L93R), was found in exon 2. The mutation was present in the father, the brother, the index patient, and the affected sister. The presence of the mutation in the propositus was verified by cloning of PCR products from genomic DNA. The mutation destroys a PstI restriction enzyme site, as confirmed in the aforementioned patients. Screening of 50 French-Canadian controls with PstI digestion did not show destruction of the restriction-enzyme site. The index patient's phenotype was severe, manifested by classic features of the illness (adrenal insufficiency, hypoparathyroidism, candidiasis, and keratoconjunctivitis with alopecia universalis), as well as by severe exocrine pancreatic insufficiency, diabetes mellitus, hepatic inflammation, growth hormone (GH) deficiency due to lymphocytic hypophysitis, and primary ovarian failure. Oral CyA (5 mg/kg/day) was initiated at 13 yr of age. After 8 months of therapy, stimulated pancreatic lipase increased 24-fold with normalization of stool fat (from 31.5 g/day to 2.5 g/day, normal(N) < 5). There was complete resolution of her photophobia, and considerable hair regrowth was diffusely apparent. Minimal side effects were noted. Our experience supports the use of oral CyA for the treatment of severe APECED-associated exocrine pancreatic failure and keratoconjunctivitis.


Use of the Child Engagement in Daily Life and Ease of Caregiving for Children to Evaluate Change in Young Children with Cerebral Palsy.
ABSTRACT Aims: Participation in family and recreational activities, self-care, and parent ease of caregiving are important outcomes for young children with cerebral palsy (CP). The aim of this study was to examine use of the Child Engagement in Daily Life and the Ease of Caregiving for Children to measure change over time. Methods: A convenience sample of 387 parents of young children with CP (18 months to 5 years of age) completed the measures twice, a mean of 12.7 months apart. Results: For the Child Engagement in Daily Life, parents of children in Gross Motor Function Classification System level I and levels II-III reported more change for the Self-care domain (medium effect) than the Family and Recreational Activities domain (small effect) and the Ease of Caregiving for Children (small effect). The change reported by parents of children in levels IV-V on all three measures was less than the criterion for a small effect. Minimal detectable change for each measure varied from 12.1 to 14.1, out of a total possible score of 100. Conclusion: Further research is recommended to determine responsiveness to change following intervention.


Gunslingers, poker players, and chickens 2: Decision-making under physical performance pressure in subelite athletes.
Having investigated the influence of acute physical exhaustion on decision-making in world-class elite athletes in Parkin et al. (2017), here a similar method is applied to subelite athletes. These subelite athletes were enrolled on a Team GB talent development program and were undergoing training for possible Olympic competition in 4-8 years. They differ from elite athletes examined previously according to expertise and age. While considered elite (Swann et al., 2015), the subelite athletes had approximately 8 years fewer sporting experience and were yet to obtain sustained success on the international stage. Additionally, the average age of the subelite sample is 20 years; thus, they are still undergoing the behavioral, cognitive, and neuronal changes that occur during the transition from late adolescence to young adulthood (Blakemore and Robbins, 2012). Previous work has used broad definitions of elite status in sport, and as such overlooked different categories within the spectrum of elite athletes (Swann et al., 2015). Therefore it is important to consider subelite athletes as a discrete point on the developmental trajectory of elite sporting expertise. This work aims to investigate the influence of physical pressure on key indicators of decision-making in subelite athletes. It forms part of a wider project examining decision-making across different stages of the developmental trajectory in elite sport. In doing so, it aims to examine how to apply and develop psychological insights useful to an elite sporting environment. 32 subelite athletes (18 males, mean age: 20 years) participated in the study. Performance across three categories of decision-making was assessed under conditions of low and high physical pressure. Decision-making under risk was measured with performance of the Cambridge Gambling Task (CGT; Rogers et al., 1999), decision-making under uncertainty with the Balloon Analogue Risk Task (BART; Lejuez et al., 2002), and fast reactive responses and inhibition via the Stop Signal Reaction Time Task (SSRT; Logan, 1994). Physical exhaustion was induced via intervals of maximal exertion exercise on a wattbike. Under pressure subelite athletes showed increased risk taking for both decisions where probability outcomes were explicit (on the CGT), and those where probability outcomes were unknown (on the BART). Despite making quicker decisions under pressure, with fewer errors, on the CGT, subelite athletes showed a reduced ability to optimally adjust betting behavior according to reward and loss contingencies. Fast reactive responses to perceptual stimuli and response inhibition did not change as a result of physical pressure. Individual responses to pressure showed a negative correlation in that a decrease in reaction times on the SSRT Task under pressure was associated with an increase in risk taking on the BART. When assessing the applicability of results based on group averages to individual athletes, 17% of the sample showed an "average" response (within 1 SD of the mean) to pressure across all three decision-making tasks. Indicators of decision-making in a sample of subelite athletes are influenced by physical pressure, with a shift toward increased indiscriminate risk taking. The influence that physical pressure has on decision-making was different to that observed in world-class elite athletes; this highlights the importance of distinguishing between athletes at the elite level (Swann et al., 2015). The application of this work to a novel subgroup of elite athletes, including the implementation of a decision-making taxonomy, is discussed.


Bisphenol F and Bisphenol S exposure during development reduce neuronal ganglia integrity and change behavioral profile of Drosophila melanogaster larvae.
The behavior and neuronal ganglia integrity of Drosophila melanogaster larvae exposed to Bisphenol F (BPF) and Bisphenol S (BPS) (0.25, 0.5 and 1 mM) was evaluated. Larvae exposed to BPF and BPS (0.5 and 1 mM) showed hyperactivity, reduced decision-making capacity and were not responsive to touch (no sensitivity to physical stimuli). There was also a reduction in the tunneling capacity induced by 1 mM of BPF and BPS (innate behaviors for survival). Behaviors resulting from changes in neuronal functioning, thermotaxis and phototaxis showed that BPS was more harmful compared to BPF. Furthermore, the concentration of 1 mM BPS generated greater damage to neuronal ganglia when compared to BPF. This difference may be related to the LC50 of the 10.04 mM BPS and 15.07 mM BPF. However, these behavioral changes presented by the larvae here are characteristic of those presented in neurodevelopmental disorders. Our findings are novel and refute the possibility that BPF and BPS are safer alternatives.


Differential responses of marine communities to natural and anthropogenic changes.
Responses of ecosystems to environmental changes vary greatly across habitats, organisms and observational scales. The Quaternary fossil record of the Po Basin demonstrates that marine communities of the northern Adriatic re-emerged unchanged following the most recent glaciation, which lasted approximately 100,000 years. The Late Pleistocene and Holocene interglacial ecosystems were both dominated by the same species, species turnover rates approximated predictions of resampling models of a homogeneous system, and comparable bathymetric gradients in species composition, sample-level diversity, dominance and specimen abundance were observed in both time intervals. The interglacial Adriatic ecosystems appear to have been impervious to natural climate change either owing to their persistence during those long-term perturbations or their resilient recovery during interglacial phases of climate oscillations. By contrast, present-day communities of the northern Adriatic differ notably from their Holocene counterparts. The recent ecosystem shift stands in contrast to the long-term endurance of interglacial communities in face of climate-driven environmental changes.


A multicenter phase II randomized trial of durvalumab (MEDI-4736) versus physician's choice chemotherapy in recurrent ovarian clear cell adenocarcinoma (MOCCA).
The optimal treatment of recurrent ovarian clear cell carcinoma remains unknown. There is increasing rationale to support the role of immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in ovarian clear cell carcinoma. To evaluate the efficacy of durvalumab (MEDI-4736) compared with standard chemotherapy in patients with recurrent ovarian clear cell carcinoma. Patients with recurrent ovarian clear cell carcinoma treated with durvalumab will have improved progression-free survival compared with those treated with chemotherapy of physician's choice. The MOCCA study is a multicenter, open-label, randomized phase II trial in patients with recurrent ovarian clear cell carcinoma, which recruited from eight sites across Gynecologic Cancer Group Singapore (GCGS), Korean Gynecologic-Oncology Group (KGOG), and Australia New Zealand Gynecological Oncology Group (ANZGOG). Enrolled patients were randomized in a 2:1 ratio to receive durvalumab or physician's choice of chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. Eligible patients required histologically documented diagnosis of recurrent ovarian clear cell carcinoma, as evidenced by WT1 negativity. All patients must have been of Eastern Cooperative Oncology Group (ECOG) performance status 2 or better, and have had previous treatment with, and progressed or recurred after prior platinum-based chemotherapy. No more than four prior lines of treatment were allowed and prior immune checkpoint inhibitor treatment was not permitted. The primary endpoint was the median progression-free survival following treatment with durvalumab, compared with physician's choice of chemotherapy. Progression-free survival was defined as the time from the first day of treatment to the first observation of disease progression, or death due to any cause, or last follow-up. The target sample size was 46 patients. Accrual has been completed and results are expected to be presented by mid-2021. Clinicaltrials.gov: NCT03405454.


Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility.
The coordinated interplay of substrate adhesion and deadhesion is necessary for cell motility. Using MCF-7 cells, we found that insulin-like growth factor I (IGF-I) induces the adhesion of MCF-7 to vitronectin and collagen in a dose- and time-dependent manner, suggesting that IGF-I triggers the activation of different integrins. On the other hand, IGF-I promotes the association of insulin receptor substrate 1 with the focal adhesion kinase (FAK), paxillin, and the tyrosine phosphatase SHP-2, resulting in FAK and paxillin dephosphorylation. Abrogation of SHP-2 catalytic activity with a dominant-negative mutant (SHP2-C>S) abolishes IGF-I-induced FAK dephosphorylation, and cells expressing SHP2-C>S show reduced IGF-I-stimulated chemotaxis compared with either mock- or SHP-2 wild-type-transfected cells. This impairment of cell migration is recovered by reintroduction of a catalytically active SHP-2. Interestingly, SHP-2-C>S cells show a larger number of focal adhesion contacts than wild-type cells, suggesting that SHP-2 activity participates in the integrin deactivation process. Although SHP-2 regulates mitogen-activated protein kinase activity, the mitogen-activated protein kinase kinase inhibitor PD-98059 has only a marginal effect on MCF-7 cell migration. The role of SHP-2 as a general regulator of cell chemotaxis induced by other chemotactic agents and integrins is discussed.


Reproducibility of neuroendocrine lung tumor classification.
For a tumor classification scheme to be useful, it must be reproducible and it must show clinical significance. Classification of neuroendocrine lung tumors is a difficult problem with little information about interobserver reproducibility. We sought to evaluate the classification of typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell carcinoma (SCC) tumors as proposed by W.D. Travis et al (Am J Surg Pathol 15:529, 1991). Forty neuroendocrine tumors were retrieved from the Armed Forces Institute of Pathology (AFIP) files and independently evaluated by five lung pathologists and classified as TC, AC, LCNEC, or SCC (pure SCC, mixed small cell/large cell, and combined SCC). A single hematoxylin and eosin-stained slide from each case was reviewed. Each participant was provided a set of tables summarizing the criteria for separation of the four major categories. Agreement was regarded as unanimous if all five pathologists agreed, a majority if four agreed, and a consensus if three or more pathologists agreed. The kappa statistic was calculated to measure the degree of agreement between two observers. A consensus diagnosis was achieved in all 40 cases (100%), a majority agreement in 31 of 40 (78%), and unanimous agreement in 22 of 40 (55%) of cases. Unanimous agreement occurred in seven of SCC (70%), seven of TC (58%), four of AC (50%), and four of LCNEC (40%). A majority diagnosis was achieved in 11 of 12 (92%) of TC, 9 of 10 (90%) of SCC, 6 of 8 (75%) of AC, and 5 of 10 (50%) of LCNEC. Most of the kappa values were 0.70 or greater, falling into the substantial agreement category. The most common disagreements fell between LCNEC and SCC, followed by TC and AC, and AC and LCNEC. The highest reproducibility occurred for SCC and TC, with disagreement in 8% and 10% of the diagnoses, respectively. For TC, 10% of the diagnoses rendered were AC. For AC, 15% of the diagnoses were rendered as TC, with 2.5% called LCNEC and 2.5% called SCC. For LCNEC, 18% and 4% of the diagnoses were called SCC and AC, respectively. For SCC, 4% of the diagnoses were called AC and 4% were called LCNEC. Thus, using the classification scheme tested, a consensus diagnosis can be achieved for virtually all neuroendocrine lung tumors with substantial agreement between experienced lung pathologists. Classification of NE tumors is most reproducible for classification of TC and SCC but less reproducible for AC and LCNEC. These results indicate a need for more careful definition and application of criteria for TC versus AC and SCC versus LCNEC.


Synthesis biological evaluation and molecular docking of isatin hybrids as anti-cancer and anti-microbial agents.
Isatin, known as 1H-indole-2,3-dione, was originally recognised as a synthetic molecule until its discovery in the fruits of the cannonball tree, Couroupita guianensis. It is naturally occurring in plants of the genus Isatis and serves as a metabolic derivative of adrenaline in humans. Isatin possesses significant pharmacological importance, and its synthetic versatility has prompted extensive interest in its derivative compounds due to their diverse biological and pharmacological properties. These derivatives represent a valuable class of heterocyclic compounds with potential applications as precursors for synthesizing numerous valuable drugs. In the pursuit of advancing our research on isatin hybrids, we investigate the utilisation of readily available hydrazonoindolin-2-one and isatin as starting materials for the synthesis of a wide range of analogues. Characterisation of the synthesized compounds was carried out through various analytical techniques. Furthermore, the obtained compounds were subjected to extensive testing to evaluate their anticancer and antimicrobial activities. Specifically, their efficacy against key proteins, namely Staphylococcus aureus protein (PDB ID: 1JIJ), Escherichia coli protein (PDB ID: 1T9U), Pseudomonas aeruginosa protein (PDB ID: 2UV0), and Acinetobacter baumannii protein (PDB ID: 4HKG), was examined through molecular docking calculations. Several molecules, such as 3, 4, 6, 16, and 19, displayed remarkable activity against the renal cancer cell line UO-31. Additionally, the results of antimicrobial activity testing revealed that compound 16 exhibited significant cytotoxicity against Candida albicans and Cryptococcus neoformans. Subsequently, ADME/T calculations were performed to gain insights into the potential effects and reactions of these molecules within human metabolism. This comprehensive study provides valuable insights into the potential pharmacological applications of isatin derivatives and underscores their significance in drug development.


Nisin production in realkalized fed-batch cultures in whey with feeding with lactose- or glucose-containing substrates.
Nisin production by Lactococcus lactis CECT 539 was followed in batch cultures in whey supplemented with different concentrations of glucose and in two realkalized fed-batch fermentations in unsupplemented whey, which were fed, respectively, with concentrated solutions of lactose and glucose. In the batch fermentations, supplementation of whey with glucose inhibited both the growth and bacteriocin production. However, fed-batch cultures were characterized with high productions of biomass (1.34 and 1.51 g l(-1)) and nisin (50.6 and 60.3 BU ml(-1)) in comparison to the batch fermentations in unsupplemented whey (0.48 g l(-1) and 22.5 BU ml(-1)) and MRS broth (1.59 g l(-1) and 50.0 BU ml(-1)). In the two realkalized fed-batch fermentations, the increase in bacteriocin production parallels both the biomass production and pH drop generated in each realkalization and feeding cycle, suggesting that nisin was synthesized as a pH-dependent primary metabolite. A shift from homolactic to heterolactic fermentation was observed at the 108 h of incubation, and other metabolites (acetic acid and butane-2,3-diol) in addition to lactic acid accumulated in the medium. On the other hand, the feeding with glucose improved the efficiencies in glucose, nitrogen, and phosphorus consumption as compared to the batch cultures. The realkalized fed-batch fermentations showed to be an effective strategy to enhance nisin production in whey by using an appropriate feeding strategy to avoid the substrate inhibition.


[Neural basis of learning new movements: evolution of classical concepts].
According to classical consepts, the role of the motor cortex in performance of skilled movements of distal parts of extremities is confined to control of appropriate motoneurons by the "point-to-point" principle. However, much evidence of plasticity of the motor cortex and its active role in motor learning appeared in last decade. Fos-gene expression in the motor cortex was found to accompany learning a skill. Strengthening of horizontal pathways in layers II-III was revealed, and cholinergic input to tese layers was found to be important. The imaging data show that activity of the motor cortex increases during motor practice as well. This raises the question of specificity of the motor cortex in the motor learning per se. During acquisition of new movements some previously used synergies prevent the necessary coordination from being learned, so they must be suppressed in the process of motor learning. Investigations of central mechanisms of coordination interference in humans are still at the beginning. However, there are some animal models of reorganization and suppression of interfering synergies. The reorganization and suppression of coordination preventing realization of a new movement is shown to be a specific function of the motor cortex. After automation of new synergies the cortical control is still present, as distinct from the learned movements, which do not require suppression of interfering synergies. However, it does not mean that the conscious control of the performance is still present.


The Clinicopathologic Features and Prognostic Impact of ALK Positivity in Patients with Resected Gastric Cancer.
Rearrangement of ALK is an established driver aberration in lung cancer. Accordingly, this study attempted to determine the frequency and prognostic impact of ALK alterations in patients with surgically resected gastric cancer. The study evaluated ALK alterations in whole tumor sections of 455 curatively resected gastric cancers via immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Any expression of ALK protein (1+, 2+, 3+ by IHC) was considered as evidence of ALK positivity (ALK+), and the relationship between ALK positivity and clinicopathologic parameters, including survival outcome, was analyzed. Of the 455 tumors, 38 (8.4 %) were ALK positive, as measured by IHC. Among the ALK+ patients, two displayed break-apart signals of 5 and 11 % on FISH, respectively. The ALK+ patients were younger (57 vs. 61 years; P = 0.02) and more likely to exhibit a signet ring cell component. Moreover, as ALK intensity measured by IHC increased, so did the proportion of signet ring cells in tumors (defined as ≥10 % of tumor cells; P = 0.02). In terms of survival outcome, the ALK+ patients displayed worse disease-free survival (DFS) and overall survival (OS) than the ALK- patients (P = 0.010 for DFS; P = 0.023 for OS). Multivariate analysis demonstrated that ALK+ gastric cancer patients were at an increased risk of recurrence and death after adjustment for sex, age, tumor location, stage, adjuvant chemotherapy, histology, and epidermal growth factor receptor 2 (HER2) positivity (P = 0.04 for DFS; P = 0.02 for OS). The findings showed ALK positivity to be an independent negative prognostic factor in surgically resected gastric cancers associated with signet ring cell histology.


Dalbavancin Use in the Emergency Department Setting.
Background: Although dalbavancin's (DBV's) long half-life and one-time dosing strategy confer ideal administration in the ambulatory setting, the optimal role of DBV in the management of acute bacterial skin and skin structure infections (ABSSSIs) remains to be elucidated. Objectives: The primary objective of this study was to compare treatment outcomes of ABSSSI between patients who received DBV in the emergency department (ED) as part of standard care versus patients who received DBV as part of a telehealth program. Methods: This was a retrospective cohort study evaluating patients who received DBV at 3 urban EDs. The primary end point was the incidence of ABSSSI recurrence. Secondary outcomes included need for hospital admission and ED length of stay (LOS; in hours). Results: A total of 65 ABSSSI treatment courses were included; 42 were included in the telehealth criteria (TC) cohort and 23 in the initial criteria (IC) cohort. There were 14% (6/42) infection recurrences in the TC cohort and 22% (5/23) in the IC cohort, with median time to recurrence being 4 and 14 days, respectively. Median ED LOS was significantly shorter in the TC (5 vs 25 hours, P < 0.05). Numerically fewer individuals in the TC cohort required inpatient admission (0 vs n = 2, 9%). Conclusion and Relevance: Our results suggest that patients may be safely administered DBV in an ED setting, with telehealth follow-up. Providing structured patient selection criteria is an effective method of assisting ED providers in selecting appropriate DBV candidates to limit potential recurrences and readmissions.


Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza.
Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrollment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.


Flexor muscle incursion into the carpal tunnel: a mechanism for increased carpal tunnel pressure?
To explore the hypothesis that the extrinsic finger flexor muscles have the potential to move into the proximal end of the carpal tunnel with wrist extension. The most distal muscle fibres from the deep and superficial finger flexors were measured relative to the pisiform bone in 18 cadaveric specimens. Muscle excursions during wrist extension were calculated using regression equations previously reported in the literature. The mean distances from the pisiform were 9.3 and 4.9 mm for the deep and superficial flexors, respectively. Ten flexor muscle bellies were at the level of or distal to the pisiform bone in the anatomical position, while 17 of 36 were within 5 mm. The excursions expected with wrist extension indicate that many muscles have the potential to enter the carpal tunnel, especially those within 5 mm of the pisiform bone. Comparing the expected excursions to recent pressure data, corroborating support for the pressure increase is found. Although not directly measured, the results of this study indicate incursion of the flexor muscles into the carpal tunnel space, particularly with wrist extension, is a plausible mechanism for increased carpal tunnel pressure. Proposing a mechanism by which carpal tunnel pressure is elevated during wrist and finger extension is a stepping stone to determining the etiology of the disease itself. Finding that the flexor muscle bellies appear to enter the carpal tunnel with wrist extension indicates that use of the flexor muscles should be avoided when the wrist and fingers are extended.


Phylogenetic history of patrilineages rare in northern and eastern Europe from large-scale re-sequencing of human Y-chromosomes.
The most frequent Y-chromosomal (chrY) haplogroups in northern and eastern Europe (NEE) are well-known and thoroughly characterised. Yet a considerable number of men in every population carry rare paternal lineages with estimated frequencies around 5%. So far, limited sample-sizes and insufficient resolution of genotyping have obstructed a truly comprehensive look into the variety of rare paternal lineages segregating within populations and potential signals of population history that such lineages might convey. Here we harness the power of massive re-sequencing of human Y chromosomes to identify previously unknown population-specific clusters among rare paternal lineages in NEE. We construct dated phylogenies for haplogroups E2-M215, J2-M172, G-M201 and Q-M242 on the basis of 421 (of them 282 novel) high-coverage chrY sequences collected from large-scale databases focusing on populations of NEE. Within these otherwise rare haplogroups we disclose lineages that began to radiate ~1-3 thousand years ago in Estonia and Sweden and reveal male phylogenetic patterns testifying of comparatively recent local demographic expansions. Conversely, haplogroup Q lineages bear evidence of ancient Siberian influence lingering in the modern paternal gene pool of northern Europe. We assess the possible direction of influx of ancestral carriers for some of these male lineages. In addition, we demonstrate the congruency of paternal haplogroup composition of our dataset with two independent population-based cohorts from Estonia and Sweden.


Linkage and association between HLA and 21-hydroxylase deficiency.
Congenital adrenal hyperplasia because of 21-hydroxylase deficiency is closely linked to the HLA system. The lod scores in 14 informative families are presented. Apart from linkage, the 21-hydroxylase deficiency is associated with an increase of BW47 antigen and lack of B8 antigen in patients. A family with a possible recombination between the 21-hydroxylase deficiency and the HLA complex was found, thus indicating that the 21-hydroxylase gene lies outside the HLA system and is closely linked to the HLA-DR locus.


Cytosolic free calcium increases before and oscillates during frustrated phagocytosis in macrophages.
When macrophages and neutrophils are allowed to settle onto an appropriate surface, they attach and spread in a frustrated attempt to phagocytose the substrate. Spreading is associated with extensive rearrangements of the actin cytoskeleton which resemble those occurring during phagocytosis. We have previously shown that spreading in human neutrophils is preceded by an increase in cytosolic-free calcium concentration [( Ca2+]i) (Kruskal, B. A., S. Shak, and F. R. Maxfield. 1986. Proc. Natl. Acad. Sci. USA. 83:2919-2923). To assess the generality of this signal, we measured [Ca2+]i in single thioglycollate-elicited mouse peritoneal macrophages as they spread on an immune complex-coated surface, using fura-2 microspectrofluorometry. A [Ca2+]i increase always precedes spreading. This increase can involve several (up to 8) [Ca2+]i spikes, with an average peak value of 387 +/- 227 nM (mean +/- SD, n = 92 peaks in 24 cells), before spreading is detected. Neither spreading nor the magnitude of these spikes is significantly altered by removal of extracellular calcium. Many of the spreading macrophages exhibit periodic [Ca2+]i increases before and during spreading. The proportion which does so varies among experiments from 0 to 90%, but it is frequently greater than 40%. The largest number of cells (approximately 25%) exhibited only a single peak. In 13 cells that showed more than 10 peaks, the median period was 29 s (range 19-69 s). The average peak [Ca2+]i was 385 +/- 266 nM (mean +/- SD, n = 208 peaks in 14 cells). The calcium producing these increases is derived from intracellular pools. The oscillations occur with spreading on either opsonized or nonopsonized surfaces. The function of these oscillations is not clear, but the large number of cells which exhibit them suggest that they may be important to macrophage function.


The influence of obesity and gender on outcome after reversed L-shaped osteotomy for hallux valgus.
Hallux valgus deformity (HV) affects around every fourth individual, and surgical treatment is performed in every thousandth person. There is an ongoing quest for the best surgical management and reduction of undesirable outcomes. The aim was to explore associations of obesity and gender with radiological and clinical outcome after reversed L-shaped osteotomy (ReveL) for HV. This study was carried out in a retrospective cohort design at a single University Hospital in Switzerland between January 2004 and December 2013. It included adult patients treated with ReveL for HV. The primary exposure was body mass index (BMI) at the time of ReveL. The secondary exposure was gender. The primary outcome was radiological relapse of HV (HV angle [HVA] > 15 degrees [°]) at the last follow-up. Secondary outcomes were improvable patient satisfaction, complication, redo surgery, and optional hardware removal. Logistic regression analysis adjusted for confounders. The median weight, height, and BMI were 66.0 (interquartile range [IQR] 57.0-76.0) kilograms (kg), 1.65 (IQR 1.60-1.71) metres (m), and 24.0 (IQR 21.3-27.8) kg/m2. Logistic regression analysis did not show associations of relapse with BMI, independent of age, gender, additional technique, and preoperative HVA (adjusted odds ratio [ORadjusted] = 1.10 [95% (%) confidence interval (CI) = 0.70-1.45], p = 0.675). Relapse was 91% more likely in males (ORadjusted = 1.91 [95% CI = 1.19-3.06], p = 0.007). Improvable satisfaction was 79% more likely in males (ORadjusted = 1.79 [CI = 1.04-3.06], p = 0.035). Hardware removal was 47% less likely in males (ORadjusted = 0.53 [95% CI 0.30-0.94], p = 0.029). In this study, obesity was not associated with unsatisfactory outcomes after ReveL for HV. This challenges the previous recommendation that preoperative weight loss may be necessary for a successful surgical treatment outcome. Males may be informed about potentially higher associations with unfavourable outcomes. Due to the risk of selection bias and lack of causality, findings may need to be confirmed with clinical trials.


Construction of a nomogram risk prediction model for PICC-related venous thrombosis and its application.
To explore the risk factors of the peripherally inserted central catheter (PICC)-related venous thrombosis and correspondingly construct a nomogram risk prediction model. The clinical data of 401 patients receiving PICC catheterization in our hospital from June 2019 to June 2022 were retrospectively analyzed. The independent influencing factors for venous thrombosis were predicted using logistic regression analysis, and significant indicators were screened to construct a nomogram for predicting PICC-related venous thrombosis. The difference in predictive efficacy between simple clinical data and nomogram was analyzed using a receiver operating characteristic (ROC) curve, and the nomogram was internally validated. Single-factor analysis showed that catheter tip position, plasma D-dimer concentration, venous compression, malignant tumor, diabetes, history of thrombosis, history of chemotherapy, and history of PICC/CVC catheterization were correlated with PICC-related venous thrombosis. Further multi-factor analysis revealed that catheter tip position, plasma D-dimer elevation, venous compression, history of thrombosis and history of PICC/CVC catheterization were the risk factors for PICC-related venous thrombosis. Based on binary logistic regression analysis, a nomogram prediction model for PICC-related venous thrombosis was constructed. The area under the curve (AUC) was 0.876 (95%CI: 0.818-0.925), with a statistically significant difference (P < 0.01). The independent risk factors for PICC-related venous thrombosis are screened out, including catheter tip position, plasma D-dimer elevation, venous compression, history of thrombosis and history of PICC/CVC catheterization, and a nomogram prediction model with good effect is constructed to predict the risk of PICC-related venous thrombosis.


Erasing and blurring memories: The differential impact of interference on separate aspects of forgetting.
Interference disrupts information processing across many timescales, from immediate perception to memory over short and long durations. The widely held similarity assumption states that as similarity between interfering information and memory contents increases, so too does the degree of impairment. However, information is lost from memory in different ways. For instance, studied content might be erased in an all-or-nothing manner. Alternatively, information may be retained but the precision might be degraded or blurred. Here, we asked whether the similarity of interfering information to memory contents might differentially impact these 2 aspects of forgetting. Observers studied colored images of real-world objects, each followed by a stream of interfering objects. Across 4 experiments, we manipulated the similarity between the studied object and the interfering objects in circular color space. After interference, memory for object color was tested continuously on a color wheel, which in combination with mixture modeling, allowed for estimation of how erasing and blurring differentially contribute to forgetting. In contrast to the similarity assumption, we show that highly dissimilar interfering items caused the greatest increase in random guess responses, suggesting a greater frequency of memory erasure (Experiments 1-3). Moreover, we found that observers were generally able to resist interference from highly similar items, perhaps through surround suppression (Experiments 1 and 4). Finally, we report that interference from items of intermediate similarity tended to blur or decrease memory precision (Experiments 3 and 4). These results reveal that the nature of visual similarity can differentially alter how information is lost from memory. (PsycINFO Database Record


Humoral protection against mosquito bite-transmitted Plasmodium falciparum infection in humanized mice.
A malaria vaccine that prevents infection will be an important new tool in continued efforts of malaria elimination, and such vaccines are under intense development for the major human malaria parasite Plasmodium falciparum (Pf). Antibodies elicited by vaccines can block the initial phases of parasite infection when sporozoites are deposited into the skin by mosquito bite and then target the liver for further development. However, there are currently no standardized in vivo preclinical models that can measure the inhibitory activity of antibody specificities against Pf sporozoite infection via mosquito bite. Here, we use human liver-chimeric mice as a challenge model to assess prevention of natural Pf sporozoite infection by antibodies. We demonstrate that these mice are consistently infected with Pf by mosquito bite and that this challenge can be combined with passive transfer of either monoclonal antibodies or polyclonal human IgG from immune serum to measure antibody-mediated blocking of parasite infection using bioluminescent imaging. This methodology is useful to down-select functional antibodies and to investigate mechanisms or immune correlates of protection in clinical trials, thereby informing rational vaccine optimization.


Parents, teachers and peer relations as predictors of risk behaviors and mental well-being among immigrant and Israeli born adolescents.
This study examines the roles of parents (monitoring, involvement and support at school), teachers (support) and peers (excess time spent with friends, peer rejection at school) in predicting risk behaviors (smoking and drinking) and mental well-being among 3499 Israeli-born and 434 immigrant adolescents ages 11, 13 and 15, in the 2006 WHO Health Behavior in School-Aged Children cross-national survey. Structural Equation Modeling (SEM) showed that for native Israeli youth, in line with previous developmental literature, all three relationships - parents, teachers and peers - have a significant impact on both mental well-being and risk behaviors. However, for immigrant adolescents, it was the school environment (parental support at school, teacher support and peer relationships) that proved to be the significant predictor of risk behaviors and mental health outcomes. These findings suggest that the school is an important social support in the health and mental well-being of immigrant schoolchildren.


Absence of significant adverse events following thalidomide administration in bitches diagnosed with mammary gland carcinomas.
The aim of the study was to evaluate the incidence of adverse events (AEs) in female dogs diagnosed with advanced clinical stage mammary gland neoplasms following treatment with thalidomide. A prospective analysis of 29 female dogs treated with a high dose (HD) of 20 mg/kg/day of thalidomide for three months followed by a low dose (LD) of 10 mg/kg/day of thalidomide for three months was performed. All patients underwent physical examination, complete blood count, serum biochemistry profile, thoracic radiographs, and abdominal ultrasound analysis before the treatment and after the HD and LD. Clinical AEs were absent in 16/29 (55.17 per cent) patients following HD. An initial 3-5 day period of somnolence was described in 4/29 (13.79 per cent), prolonged somnolence in 5/29 (17.24 per cent), a short period of somnolence lasting only a few hours in 3/29 (10.34 per cent), and difficulty to rouse was described in 5/29 (17.24 per cent) cases. Two patients (6.89 per cent) presented with prolonged somnolence that interfered with activities of daily living, resulting in anticipation of the dose reduction to the proposed LD after 15 days of the HD treatment. Following dose reduction, AE improvement was observed in all patients. Albeit remaining within the reference ranges, erythrocytes, haematocrit, total leucocyte count, neutrophils, lymphocytes, monocytes and γ-glutamyltranspeptidase showed significant alteration associated to thalidomide treatment.


The nominative technique: a new method of estimating heroin prevalence.
Over the years, nominative estimates of heroin prevalence have been consistently higher than self-reports of heroin use. During this time, nominative data have generally followed mainstream patterns of drug use: nominative estimates for young adults and for males are higher than nominative estimates for older persons, youth, and females; moreover, the recent downward trends in drug use have been replicated by the nominative heroin data. Thus, the overall picture presented by the nominative data--similar patterns but higher levels of prevalence--seems to support the validity of the new approach. Nevertheless, considerable caution should be exercised in interpreting nominative data. This is chiefly because a substantial minority of nominators cannot report the number of other close friends of the heroin user who also "know." While missing data has been handled by a conservative imputation rule, the fact that so many persons are unable to provide an answer to this key question casts doubt on the accuracy of the answers that were given. In fact, the nominative approach might tend to produce over-estimates, because of the potential for undercounts of the numbers of others who "know." Additional tests of validity should be performed, such as application of the nominative approach to nonsensitive behaviors or minimally sensitive behaviors, such as marijuana use or perhaps cocaine use. Certainly, the overall validity of the nominative heroin data would be supported if in future surveys new nominative heroin estimates for relatively unstigmatized forms of drug use proved to be similar to self-reported levels of use, thus pointing to the unique difference in estimates that might be observed for heroin. Finally, in interpreting the heroin estimates presented here, it should be remembered that both the nominative and self-report estimates refer to heroin use in the household population of the United States. Thus, many heroin addicts and other users who reside in various unconventional living arrangements would not be included in the counts presented here. Among the excluded groups are transients residing in rooming houses or "crashing" in the home of one "friend" after another or who are incarcerated in jails or confined to residential drug treatment centers. This is a caution for interpreting the estimates presented in this paper, not a criticism of the nominative technique itself.(ABSTRACT TRUNCATED AT 400 WORDS)


Clinical classification of childhood glaucomas.
An updated classification of the primary and secondary childhood glaucomas is offered for clinical use, and associated systemic diseases are included to enable their early recognition in children with known glaucoma. Approximately 650 clinical records of patients with pediatric glaucoma were reviewed for type of glaucoma and associated systemic disease. A literature search was done for additional reported causes of childhood glaucoma. Previous classifications of pediatric glaucomas were also reviewed. Pertinent references to support inclusion of each clinical entity in the updated classification are included. A comprehensive and referenced classification of the pediatric glaucomas was enabled by this review. A comprehensive, etiologically based classification of the pediatric glaucomas is now available to assist with the recognition of the many causes of primary and secondary glaucoma in childhood and to support the selection of specific treatment choices.


Extracorporeal membrane oxygenation to support adult patients with cardiac failure: predictive factors of 30-day mortality.
Adult patients supported on extracorporeal membrane oxygenation (ECMO) are very sick and many complications are often present in each single patient; therefore, it is not always easy to find some risk factors that can predict the early outcome. This retrospective study reports our experience in ECMO support treatment in adult cardiac patients suffering from cardiac failure (CF) in which one or more predictive factors of 30-day mortality were analyzed. Between January 2002 and August 2009, 42 consecutive adult cardiac patients with cardiogenic shock (mean age 64.3+/-11.3 years) were supported on ECMO for >2 days. They were divided into patients who had a survival <30 days (n=20) and patients who survived >30 days (n=22). Twenty-nine patients (69%) survived on ECMO. Sixteen patients were discharged with a survival rate of 38.1%. The overall mean ECMO duration was 7.9+/-5.3 days. The following variables were significantly different between the two groups: number of platelets and packed red blood cells (PRBCs) transfused per day during ECMO (P=0.002 and P=0.003), blood lactate levels 48 h and 72 h after the initiation of ECMO (P=0.01 and P=0.04), indexed blood flow after 48 h and 72 h (P=0.01 and P<0.0001), liver failure (P=0.001) and multiorgan failure (P=0.002). Stepwise logistic regression identified that blood lactate levels at 48 h and number of PRBCs transfused were associated with 30-day mortality [P=0.019, odds ratio (OR) =2.16; 95% confidence interval (CI)=1.13-4.14 and P=0.008, OR=1.08; 95% CI=1.02-1.14, respectively]. The predicted probability of mortality would be 52% when blood lactate levels are >3 mmol/l after 48 h. The blood lactate level at 48 h and PRBCs transfused per day can be considered as important parameters to predict the mortality in adult cardiac patients supported by ECMO for CF.


The medical dictionary for regulatory activities (MedDRA).
The International Conference on Harmonisation has agreed upon the structure and content of the Medical Dictionary for Regulatory Activities (MedDRA) version 2.0 which should become available in the early part of 1999. This medical terminology is intended for use in the pre- and postmarketing phases of the medicines regulatory process, covering diagnoses, symptoms and signs, adverse drug reactions and therapeutic indications, the names and qualitative results of investigations, surgical and medical procedures, and medical/social history. It can be used for recording adverse events and medical history in clinical trials, in the analysis and tabulations of data from these trials and in the expedited submission of safety data to government regulatory authorities, as well as in constructing standard product information and documentation for applications for marketing authorisation. After licensing of a medicine, it may be used in pharmacovigilance and is expected to be the preferred terminology for international electronic regulatory communication. MedDRA is a hierarchical terminology with 5 levels and is multiaxial: terms may exist in more than 1 vertical axis, providing specificity of terms for data entry and flexibility in data retrieval. Terms in MedDRA were derived from several sources including the WHO's adverse reaction terminology (WHO-ART), Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART), International Classification of Diseases (ICD) 9 and ICD9-CM. It will be maintained, further developed and distributed by a Maintenance Support Services Organisation (MSSO). It is anticipated that using MedDRA will improve the quality of data captured on databases, support effective analysis by providing clinically relevant groupings of terms and facilitate electronic communication of data, although as a new tool, users will need to invest time in gaining expertise in its use.


Chromatin-bound and free forms of poly(adenylic acid) polymerase in rat hepatic nuclei.
Isolated rat hepatic nuclei were shown to contain poly(A) polymerase in two distinct physiologically active forms. One form was associated with the chromatin fraction and was dependent on endogenous RNA, presumably mRNA. The other activity was localized in the nuclear sap in a 'free' form and was stimulated almost 30-40-fold by exogenously added poly(A). Isolated nucleoli were devoid of significant poly(A)-synthesizing activity.


Physical and psychological implications in a multiple and preterm caesarean section. A case report.
Cesarean section (CS) in Italy has continuously increasing rates. Due to the primary CS, the repeated CS have shown a superimposable trend. Consequently, a number of pathologies are related to such surgery among which placenta previa, dehiscence of previous scar, placenta accreta and preterm delivery. The purpose of this case report is to discuss the physical and psychological implications correlated with a very unusual case of a consecutive seventh CS in the same pregnant woman associated with several diseases: preterm delivery, fetal distress, intrauterine growth retardation (IUGR) (-4 weeks), central placenta previa with metrorrhagia, dehiscence of hysterectomic scar. In spite of the therapy (antifibrinolytic, tocolytic drugs, iron, folates, betamethasone) a preterm CS could not be avoided. Surgery was challenging; hysterectomy was avoided and the mother followed a normal post-operative course, whereas fetal distress and IUGR did not allow the survival of the newborn. A review of the literature regarding the clinical management and psychological aspects of a pregnant woman undergoing multiple complicated CS with the aforementioned disorders will be undertaken.


Eustress and Distress: Neither Good Nor Bad, but Rather the Same?
The terms "eustress" and "distress" are widely used throughout the scientific literature. As of February 2020, 203 items in the Web of Science show up in a search for "eustress," however, there are almost 16 400 items found in a search for the term "distress." Based on the reasoning in this article, however, it is believed there is no such thing as eustress or distress. The adaptation reaction of an organism under stress is not intrinsically good or bad, and its effect on health or performance depends on a plethora of other interactions of the body with the environment as well as on the history of such interactions. The vagueness of the terms "eustress/distress" has historically led to vast differences in the perception and application of the terms across disciplines. While psychology or sociology perceive eustress as something inextricably linked to positive perception and enhanced cognition, biomedicine perceives eustress as generally associated with better survival, health, or increased longevity, no matter how the event is perceived. In this paper, the authors review the current understanding of the term "eustress" in different fields, discuss possible implications of its misleading use, and suggest that the term may be replaced by "stress" only.


Antiviral therapy in children with varicella zoster virus and herpes simplex virus infections.
A small number of antiviral drugs are available for the treatment of varicella zoster virus (VZV) and herpes simplex virus (HSV) infections in children. This review presents pharmacokinetic data on the following selected antiviral agents: aciclovir, valaciclovir, famciclovir, cidofovir and foscarnet. Support and current recommendations for the treatment of selected VZV and HSV infections in children will also be reviewed.


Is oppositional defiant disorder a meaningful diagnosis in adults? Results from a large sample of adults with ADHD.
We examined the prevalence and clinical characteristics of oppositional defiant disorder (ODD) in a sample of clinically referred adults with attention deficit hyperactivity disorder (ADHD). Subjects were consecutively referred adults with a DSM-III R/IV diagnosis of ADHD with or without ODD. Nearly half of subjects (43%) had a history of ODD. Subjects with a childhood history of ODD had increased risk for bipolar disorder, multiple anxiety disorders, and substance use disorders relative to the ADHD subjects without ODD. We concluded, as in children with ODD, adults with a childhood history of ODD have high rates of psychiatric comorbidity and more impaired psychosocial functioning than those without this condition. A better understanding of the course, phenomenology, and clinical significance of ODD in adults is needed to better understand therapeutic approaches for this disorder.


Molecular electronic level alignment at weakly coupled organic film/metal interfaces.
Electronic level alignment at interfaces of molecular materials with inorganic semiconductors and metals controls many interfacial phenomena. How the intrinsic properties of the interacting systems define the electronic structure of their interface remains one of the most important problems in molecular electronics and nanotechnology that can be solved through a combination of surface science experimental techniques and theoretical modeling. In this article, we address this fundamental problem through experimental and computational studies of molecular electronic level alignment of thin films of C(6)F(6) on noble metal surfaces. The unoccupied electronic structure of C(6)F(6) is characterized with single molecule resolution using low-temperature scanning tunneling microscopy-based constant-current distance-voltage spectroscopy. The experiments are performed on several noble metal surfaces with different work functions and distinct surface-normal projected band structures. In parallel, the electronic structures of the quantum wells (QWs) formed by the lowest unoccupied molecular orbital state of the C(6)F(6) monolayer and multilayer films and their alignment with respect to the vacuum level of the metallic substrates are calculated by solving the Schrödinger equation for a semiempirical one-dimensional (1D) potential of the combined system using input from density functional theory. Our analysis shows that the level alignment for C(6)F(6) molecules bound through weak van der Waals interactions to noble metal surfaces is primarily defined by the image potential of metal, the electron affinity of the molecule, and the molecule surface distance. We expect the same factors to determine the interfacial electronic structure for a broad range of molecule/metal interfaces.


Subjective and objective responses to ethanol in moderate/heavy and light social drinkers.
Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking. We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations. Moderate/heavy drinkers reported greater stimulant-like and fewer sedative-like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects. These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant-like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant-like effects during the ascending limb and lesser sedative-like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.


Quality of care in postoperative pain management: what is realistic in clinical practice?
This paper presents a study describing nurses' assessment of whether it was realistic to carry out good quality of care in postoperative pain management. Further, the study compared their assessment with the quality of care actually performed in clinical practice as assessed by both patients and nurses. Three questionnaires were used; one for patients (n = 198) and two for nurses (n = 63). Nurses and patients responded to similar questions; the patients assessed the quality of care they had received, and the nurses assessed the quality of care they had delivered. The nurses also responded to questions concerning whether the different aspects of good quality of care were realistic to carry out in practice. The results show that in several important aspects of postoperative pain management, both patients and nurses assessed the quality of care to be lower than the nurses' assessment of what was actually possible to effectuate in clinical practice, e.g. pain assessment and information. This finding highlights the problem of applying evidence-based care in actual clinical practice.


Effects of drinking hot water, cold water, and chicken soup on nasal mucus velocity and nasal airflow resistance.
Nasal mucus velocity and nasal airflow resistance were measured in 15 healthy subjects before and at 5 and 30 minutes after drinking hot water by sip or straw, hot chicken soup by sip or straw, and cold water by sip. A sham drinking procedure with straw was also employed. Hot water by sip increased nasal mucus velocity from 6.2 to 8.4 mm per min, hot chicken soup by sip from 6.9 to 9.2 mm per min, and chicken soup by straw from 6.4 to 7.8 mm per min five minutes after administration. These increases were statistically significant compared to cold water, hot water by straw and sham. All values returned to their baseline at 30 minutes except cold water which significantly decreased the nasal mucus velocity from 7.3 to 4.5 mm per min. There were no significant changes from baseline in nasal airflow resistance 5 and 30 minutes following the above treatments. We conclude that drinking hot fluids transiently increases nasal mucus velocity in part or totally through the nasal inhalation of water vapor. Hot chicken soup, either through the aroma sensed at the posterior nares or through a mechanism related to taste, appears to possess an additional substance for increasing nasal mucus velocity. Finally, hot liquid might be superior to cold liquids in the management of fluids in upper respiratory tract infections.


Associations of Lifestyle and Anthropometric Factors With the Risk of Herpes Zoster: A Nationwide Population-Based Cohort Study.
The role of lifestyle in development of herpes zoster remains unclear. We examined whether smoking status, alcohol consumption, body mass index, or physical activity were associated with zoster risk. We followed a population-based cohort of 101,894 respondents to the 2010 Danish National Health Survey (baseline, May 1, 2010) until zoster diagnosis, death, emigration, or July 1, 2014, whichever occurred first. We computed hazard ratios for zoster associated with each exposure, using Cox regression with age as the time scale and adjusting for potential confounders. Compared with never smokers, hazards for zoster were increased in former smokers (1.17, 95% confidence interval (CI): 1.06, 1.30), but not in current smokers (1.00, 95% CI: 0.89, 1.13). Compared with low-risk alcohol consumption, neither intermediate-risk (0.95, 95% CI: 0.84, 1.07) nor high-risk alcohol consumption (0.99, 95% CI: 0.85, 1.15) was associated with zoster. We also found no increased hazard associated with weekly binge drinking versus not (0.93, 95% CI: 0.77, 1.11). Risk of zoster varied little by body mass index (referent = normal weight) and physical activity levels (referent = light level), with hazard ratios between 0.96 and 1.08. We observed no dose-response association between the exposures and zoster. The examined lifestyle and anthropometric factors thus were not risk factors for zoster.


Antibodies directed against the peroxisomal targeting signal of firefly luciferase recognize multiple mammalian peroxisomal proteins.
We have previously shown that the peroxisomal targeting signal in firefly luciferase consists of the COOH-terminal three amino acids of the protein, serine-lysine-leucine (Gould, S.J., G.A. Keller, N. Hosken, J. Wilkinson, and S. Subramani, 1989. J. Cell Biol. 108:1657-1664). Antibodies were raised against a synthetic peptide that contained this tripeptide at its COOH terminus. Immunofluorescence and immunocryoelectron microscopy revealed that the anti-peptide antibodies specifically detected peroxisomes in mammalian cells. Further characterization revealed that the antibodies were primarily directed against the COOH-terminal three amino acids of the peptide. In Western blot experiments, the antibodies recognized 15-20 rat liver peroxisomal proteins, but reacted with only a few proteins from other subcellular compartments. These results provide independent immunological evidence that the peroxisomal targeting signal identified in firefly luciferase is present in many peroxisomal proteins.


[Hernia of the external ear canal of uncommon origin].
The temporo-mandibular joint is directly related to the anterior wall of the external ear canal. Therefore, defects in this wall may lead to herniation of the soft tissues of the temporo-mandibular joint into the external ear canal. Such herniation usually is secondary to external injuries, iatrogenic trauma, neoplasms, and so on, but it may also be congenital. We report a well-documented case of temporo-mandibular joint herniation into the external ear canal of probable congenital origin.


Molecular markers predictive of chemotherapy response in colorectal cancer.
Recognition of the molecular heterogeneity of colorectal cancer (CRC) has led to the classification of CRC based on a variety of clinical and molecular characteristics. Although the clinical significance of the majority of these molecular alterations is still being ascertained, it is widely anticipated that these characteristics will improve the accuracy of our ability to determine the prognosis and therapeutic response of CRC patients. A few of these markers, such as microsatellite instability and the CpG island methylator phenotype (CIMP), show promise as predictive markers for cytotoxic chemotherapy. KRAS is a validated biomarker for epidermal growth factor receptor (EGFR)-targeted therapy, while NRAS and PI3KCA are evolving markers for targeted therapies. Multiple new actionable drug targets and potential response biomarkers are being identified on a regular basis, but most are not ready for clinical use at this time. This review focuses on key molecular features of CRCs and the application of these molecular alterations as predictive biomarkers for CRC.


Metformin-Incorporated Gelatin/Hydroxyapatite Nanofiber Scaffold for Bone Regeneration.
Tissue engineering and regenerative medicine has gradually evolved as a promising therapeutic strategy to the modern health care of aging and diseased population. In this study, we developed a novel nanofibrous scaffold and verified its application in the critical bone defect regeneration. The metformin-incorporated nano-gelatin/hydroxyapatite fibers (NGF) was produced by electrospinning, cross-linked, and then characterized by X-ray powder diffractometer and Fourier-transform infrared spectroscopy. Cytotoxicity, cell adhesion, cell differentiation, and quantitative osteogenic gene and protein expression were analyzed by bone marrow stem cells (BMSCs) from rat. Rat forearm critical bone defect model was performed for the in vivo study. The NGF were characterized by their porous structures with proper interconnectivity without significant cytotoxic effects; the adhesion of BMSCs on the NGF could be enhanced. The osteogenic gene and protein expression were upregulated. Postimplantation, the new regenerated bone in bone defect was well demonstrated in the NGF samples. We demonstrated that the metformin-incorporated NGF greatly improved healing potential on the critical-size bone defect. Although metformin-incorporated NGF had advantageous effectiveness during bone regeneration, further validation is required before it can be applied to clinical applications. Impact statement Bone is the structure that supports the rest of the human body. Critical-size bone defect hinders the regeneration of damaged bone tissues and compromises the mechanical strength of the skeletal system. Characterized by their porous structures with proper interconnectivity, the electrospinning nano-gelatin/hydroxyapatite fibrous scaffold developed in this study can greatly improve the healing potential on the critical-size bone defect. Further validation can validate its potential clinical applications.


Effect of Different Packaging Atmosphere on Microbiological Shelf Life, Physicochemical Attributes, and Sensory Characteristics of Chilled Poultry Fillets.
This trial was conducted to evaluate the effect of overwrap, vacuum, and modified atmosphere packaging (MAP) on poultry breast fillets' microbiological, biochemical shelf life and sensory attributes. The fillets were divided into 4 groups, and each of the treatments was replicated 3 times with 60 breast fillets. The first group was a control group with overwrap packaging; the second group was vacuum packed (VP); the third and fourth groups were MAP-1: 0% O2, 40% CO2, 60% N2, and MAP-2: 20% O2, 40% CO2, 40% N2. The microbiological and biochemical analyses were performed for the total viable count, coliform count, Pseudomonas count, Salmonella count, total volatile basic nitrogen (TVB-N), pH, cooking loss, color, lipid oxidation, tenderness, and sensory analysis. The data were analysed through two-way ANOVA by Minitab (Minitab 17.3.1). Meat treated with understudy MAP compositions and vacuum packaging reduced total viable count, Pseudomonas count, and total coliform count than control (p<0.05). TVB-N remained below the recommended limit throughout storage except aerobic packaging (p<0.05). Cooking loss (%) was lowered and showed non-significant results (p>0.05) between vacuum packaging and both MAP concentrations. The meat stored in MAP-2 was characterised by higher (p<0.05) visual scores. Whilst MAP-1 showed higher (p<0.05) L* values and overall acceptability. Sample packaged under aerobic packaging showed significant (p<0.05) results for b* and thiobarbituric acid reactive substances (TBARS). Meat stored in aerobic packaging showed higher (p<0.05) shear force values. The outcome of this trial may help to promote the application of understudy MAP compositions and rapid detection of microbes by biochemical analysis under local conditions.


A Carcinoid Tumor in the Urinary Bladder with Uncommon Clinicopathological Presentation.
Carcinoid tumors usually originate from the enterochromaffin cells located in gastrointestinal tract and bronchopulmonary system. They may rarely arise in the urinary bladder, where this can be eventually miscued as any other commoner bladder neoplasms. The current study was conducted to connote an uncommon clinicopathological presentation by a carcinoid tumor in the urinary bladder. A 52-year-old male, who initially experienced obstructive urinary symptoms, underwent cystourethroscopy to remove a tumor in the urinary bladder. The tumor exhibited insular, trabecular, and organoid architecture on histology without any necrosis or mitosis, stained positively with chromogranin A, and thereby, confirmed the diagnosis of a pure carcinoid tumor. Carcinoid tumors rarely arise in the urinary bladder and other genitourinary organs. But, several other and relatively more common bladder neoplasms may often deceptively simulate it. This dilemma could be resolved easily with the application of proper immunohistochemistry (IHC) in neuroendocrine tumors.


Expression of ligand-activated KIT and platelet-derived growth factor receptor beta tyrosine kinase receptors in synovial sarcoma.
The use of tyrosine kinase receptor inhibitors is increasingly becoming a valuable therapeutic alternative in tumors carrying activated tyrosine kinase receptors. In a previous study, we described a coexpression of KIT and stem cell factor (SCF) mRNA in Synovial sarcomas, (SS) and in a limited number of cases, we demonstrated the presence of an activated receptor. Here, in a wider number of cases, we investigated the expression level and phosphorylation status of two structurally related tyrosine kinase receptors, KIT and platelet-derived growth factor receptor beta (PDGFRbeta), at the light of their role as possible targets of tyrosine kinase receptors inhibitor molecules. Forty-three SS cases were analyzed for KIT and PDGFRbeta expression/activation by immunoprecipitation/Western blotting experiments. The cognate ligands, SCF and PDGFB, were detected by reverse transcription-PCR. KIT was observed in 48 and 41% (45% total) whereas PDGFRbeta in 54 and 33% (45% total) of monophasic and biphasic SS cases, respectively. With respect to the fusion transcript type SYTSSX1 and SYTSSX2, KIT was more expressed in SYTSSX1 carrying cases (48 versus 38%), whereas PDGFRbeta resulted more frequently expressed in SYTSSX2 ones (54 versus 37%). When expressed, the receptors were phosphorylated. Their ligands were detected in all of the activated cases. About 70% of the cases express one of the two activated tyrosine kinase receptors with a mutually exclusive expression trend. Coexpression is not frequent and seems to be restricted to monophasic subtype. These data indicate that a consistent fraction of this tumor type could represent a good candidate for kinase inhibitor molecules effective on KIT and PDGFRbeta where their activation is sustained by an autocrine loop.


pi conjugation across the tetrathiafulvalene core: synthesis of extended tetrathiafulvalene derivatives and theoretical analysis of their unusual electrochemical properties
A series of extended tetrathiafulvalene (TTF) derivatives bearing one or two 1,4-dithiafulven-6-yl substitutents has been prepared. The new compounds present remarkable electrochemical singularities compared with other TTF derivatives, which are strongly affected by the nature of the substitution on the lateral heterocycle(s). This unusual electrochemical behaviour follows a square-scheme sequence and is attributed to structural changes upon oxidation of the pi-donating molecules. Digital simulations of the electrochemical data have been used to reach the values of the kinetic and thermodynamic constants involved in the square scheme. Theoretical calculations establish an important contribution of a highly delocalised resonant form involving a tetravalent sulphur in oxidised species, which could justify the occurrence of an electrochemical behaviour distinct from that of TTF. Finally, third-order susceptibilities chi 3 of two of these systems, for which electron-donating and electron-withdrawing substituents coexist and are conjugated through the TTF pi system, are given.


Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn's disease.
Crohn's disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn's disease. One hundred fifty-four patients with Crohn's disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. Low bone mineral density is frequently associated with Crohn's disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.


Differential effects of transforming growth factor-beta 1 on the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in young and old human fibroblasts.
The balance between the activities of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) is an important control point in tissue remodeling. Previous studies have demonstrated elevated expression of the MMPs collagenase and stromelysin-1 by aged human diploid fibroblasts compared to early-passage cultures. We show here that aging cells display an altered response to transforming growth factor-beta 1 (TGF beta 1) that selectively affects MMP mRNA expression. In both young and old cells, phorbol myristoyl-13 acetate (PMA) induced the expression of transcripts of collagenase, stromelysin-1, gelatinase-B, TIMP-1, and TIMP-3. In young cells, TGF beta 1 reciprocally modulated PMA-induced MMP and TIMP gene expression leading to reduced levels of transcripts for the MMPs and augmented accumulation of TIMP-1 and TIMP-3 mRNAs. However, repressing effects of TGF beta 1 on collagenase, stromelysin-1, and gelatinase-B RNA expression were not apparent in old cells, though induction of the TIMP genes was unimpaired. By electrophoretic mobility shift analysis the nuclear transcription factors AP1 and serum response factor (SRF) showed reduced levels of DNA binding activities in old fibroblasts compared to young cells. A probe for the TGF beta-inhibitory element (TIE) gave equivalent levels of complexes with nuclear extracts from both types of cells, though of different mobilities. We conclude that the effects of TGF beta 1 on MMP and TIMP gene expression involve different cellular intermediaries, and suggest that altered composition or modification of TIE binding factors in aging cells may underlie the failure of TGF beta 1-mediated transcription repression. This mechanism may contribute to elevated constitutive expression of MMPs in old cells and to the connective tissue deterioration that accompanies the aging process.


Mind the mushroom: natural product biosynthetic genes and enzymes of Basidiomycota.
Covering: up to September 2020 Mushroom-forming fungi of the division Basidiomycota have traditionally been recognised as prolific producers of structurally diverse and often bioactive secondary metabolites, using the methods of chemistry for research. Over the past decade, -omics technologies were applied on these fungi, and sophisticated heterologous gene expression platforms emerged, which have boosted research into the genetic and biochemical basis of the biosyntheses. This review provides an overview on experimentally confirmed natural product biosyntheses of basidiomycete polyketides, amino acid-derived products, terpenoids, and volatiles. We also present challenges and solutions particular to natural product research with these fungi. 222 references are cited.